The beneficial and harmful effects of solar ultraviolet and visible radiation are being increasingly recognized. Photomedicine has now become a major interdisciplinary approach in dermatology and oral psoralen photochemotherapy (PUVA) has been found to be very effective in the treatment of psoriasis and other diseases. The proposed research is directed towards evaluating the possible harmful effects of PUVA therapy and in elucidating the molecular reactions of acute and chronic changes in skin (normal, photosensitivity, and cancer) that result from ultraviolet and visible radiation with DNA, RNA, and proteins. A new technique of photoaffinity labeling of enzymes using phtoreactive affinity labels mimicking folic acid is proposed. The target of this therapy is the photochemical attack of specific enzymes essential for rapid growth of psoriatic cells rather than DNA. The synthesis of several folic acid analogs containing diazoketone or aryl azido amino groups and other photoaffinity labels are proposed. Studies using new isopsoralens (e.g.., 4,5'-dimethylisopsoralen and isopsoralen) that form monofunctional adducts and show high reactivity with DNA, but no interstrand cross-links, are proposed to improve the existing photochemotherapy of psoriasis. The concept of metabolic activation of psoralens by hepatic microsomal enzymes and their interaction with DNA, RNA, or proteins to become a "chemical carcinogen" will be examined. Whether psoralens that form monofunctional adducts or bifunctional adducts with DNA are photocarcinogenic agents will be investigated. In the prevention of sunburn, aging of skin, and skin cancer, studies on photoaffinity labeling of certain ultraviolet absorbing agents with amino acids and proteins of the stratum corneum are proposed. A new approach to detect the "high-risk" population for skin cancer and studies on protection against porphyrin photosensitization by oral zinc and beta carotene in patients with porphyria are proposed. Investigations on the mechanisms of cutaneous photosensitization by porphyrins, anthracene, coal tar and chloroquin are proposed. New studies on the pathogenesis of vitiligo, refinement of photochemotherapy of vitiligo and chemotherapy of melanoma by agents that selectively localize and destroy melanocytes are also proposed.